Multiplexed latching valves for microfluidic devices and processors

ABSTRACT

Membrane valves and latching valve structures for microfluidic devices are provided. A demultiplexer can be used to address the latching valve structures. The membrane valves and latching valve structures may be used to form pneumatic logic circuits, including processors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional patent application and claims priorityto U.S. patent application Ser. No. 11/726,701, filed Mar. 21, 2007,(Atty. Docket No. UCALP066), entitled “Multiplexed Latching Valves ForComplex Microfluidic Devices and Processors”, which claims the benefitunder 35 U.S.C. 119(e) of Provisional U.S. Patent Application No.60/785,005, filed Mar. 22, 2006 (Atty. Docket No. UCALP066P), entitled“Multiplexed Latching Valves For Complex Microfluidic Devices AndProcessors”, all of which are incorporated herein by this reference intheir entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to microfluidic structures. In oneexample, the present invention relates to membrane valves and structuresthat control microfluidic flow and that can be combined to performcomplex pneumatic logical operations.

2. Description of Related Art

Modern microfluidic analysis devices having evolved considerably fromearly single-channel, single-step devices. Highly-parallel,multi-channel devices now increase throughput by performing hundreds ofassays simultaneously, and lab-on-a-chip devices now integrate complexmulti-step preparation and analysis operations into a single portableanalyzer. Devices that densely integrate both serial and paralleloperations on-chip promise to dramatically cut the time and resourcesrequired to perform a variety of assays. For example, in the field ofgenomics, the integration of operations like colony picking, sequencingsample amplification, purification, and electrophoretic analysis into ahigh-throughput parallel platform will result in significant decreasesin overall sequencing time and cost.

Realization of this goal has been slowed by the lack of valving andpumping technologies suitable for use in highly-serial, highly-parallelmicrodevices. These devices may require hundreds of valves to beactuated in parallel, while simultaneously hundreds of other valves areactuated one-by-one—an extremely demanding set of requirements. Part ofthe solution was offered by monolithic membrane valves and pumps, whichcan be fabricated in dense arrays and actuated in parallel viaintegrated pneumatic channels. However, each independent monolithicmembrane valve or set of valves requires a dedicated switchablepressure/vacuum source (typically a solenoid valve) and a separatepneumatic connection to the microfluidic device. The power consumption,cost, and size of solenoid valves preclude their use in large numbers,and excessive pneumatic connections to the microfluidic device wasteuseful on-chip space.

A single control signal could be used to control several on-chip valvesif 1) a demultiplexer is used to address which valve to open or close,and 2) each valve remains latched in its current state (open or closed)until it is set to a new state. Existing latching microvalves usebistable, buckled membranes or magnets to control flow. These silicon-or polymer-based valves are chemically and physically unsuitable formany lab-on-a-chip assays, are complex to fabricate, and cannot beeasily arrayed for parallel or multiplexed actuation. Previousdemultiplexers allow for addressing of individual microreactors in anarray but not the more-useful, arbitrary control of independent valves.Also, the row/column addressing method employed previously imposessignificant restrictions on the geometry of the device and limits thenumber of microreactors addressable by n control lines to only2^((n/2)).

SUMMARY OF THE INVENTION

In one aspect, the invention features a microfluidic latching valvestructure. The latching valve structure includes input to the structureand at least three membrane valves. Each valve includes a valve input, avalve output, and a valve control. An elastomer membrane is configuredsuch that the application of a pressure or a vacuum to the valve controlcauses the membrane to deflect to modulate a flow fluid through thevalve. Two of the valves are connected to a third valve such that asufficient vacuum at the input to the structure causes a third valve toopen and upon removal of the vacuum, the third valve remains open andsuch that a sufficient pressure at the input to the structure causes thethird valve to close and upon removal of pressure, the third valveremains closed.

Various implementations of the invention may include one or more of thefollowing features. The latching valve structure is configured tocontrol fluid flow to an on-chip microfluidic analytical device. Thelatching valve structure is configured to control a fluidic process ofan assay of a microfluidic device. The latching valve structure furtherincludes a demultiplexer configured to control an array of latchingvalves structured to performing an assay.

In another aspect, the invention features a microfluidic logic circuit.The logic circuit includes an array of membrane valves. Each valveincludes a valve input, a valve output, a valve control, and anelastomer membrane wherein the application of a pressure or a vacuum cancause the membrane to deflect to modulate a flow of fluid through thevalve. The membrane valves are connected in fluid communication witheach other such that a pneumatic input to the array is logicallyoperated upon to produce a pneumatic output.

Various implementations of the invention may include one or more of thefollowing features. The array of membrane valves includes two membranevalves configured to form an AND gate or an OR gate. The array ofmembrane valves is configured to form a NAND gate or an XOR gate. Thearray of membrane valves is configured to form a buffer circuit. Thearray of membrane valves is configured to form a ripple carrier adder.

The invention can include one or more of the following advantages. Largenumbers of multiplexed latching valve structures can be independentlycontrolled by a small number of pneumatic lines, thereby reducing thesize, power consumption, and cost of microfluidic lab-on-a-chip devices.That is, the latching valve structures can control microfluidic flowwith a minimum of chip to world pneumatic interfaces. This includes butgoes beyond multiplexers. These structures also enable the developmentof pneumatic logic processors. Monolithic valves and structures can beconfigured to function as transistors in pneumatic digital logiccircuits. Using the analogy with N-channel MOSFETs, networks ofpneumatically actuated microvalves can provide pneumatic digital logicgates (AND, OR, NOT, NAND, and XOR). These logic gates can be combinedto form complex logical circuits like ripple carry adders. The inventionalso enables the development of digital pneumatic computing and logicsystems that are immune to electromagnetic interference.

These and other features and advantages of the present invention will bepresented in more detail in the following specification of the inventionand the accompanying figures, which illustrate by way of example theprinciples of the invention.

BRIEF DESCRIPTION OF DRAWINGS

The invention may best be understood by reference to the followingdescription taken in conjunction with the accompanying drawings thatillustrate specific embodiments of the present invention.

FIG. 1 is a diagrammatic exploded view of a membrane valve.

FIG. 1B is a diagrammatic view of an assembled membrane valve.

FIGS. 1C and 1D are diagrammatic cross-sectional views of the assembledvalve of FIG. 1B shown in the closed and open positions, respectively.

FIG. 2A is a diagrammatic illustration of the assembly of avacuum-latching (V-latching) valve structure.

FIG. 2B is a diagrammatic representation of the assembled V-latchingvalve structure of FIG. 2A.

FIGS. 3A and 3B are diagrammatic representations of the structure andoperation of a V-latching valve and a PV-latching valve, respectively.

FIG. 4A is a graphical representation of the flow rates through aV-latching valve being set open and closed by vacuum and pressure pulsesof varying durations.

FIG. 4B is a graphical representation of flow rates through the sameV-latching valve after being latched closed or open by a 120 ms pressureor vacuum pulse.

FIG. 5A is a graphical representation of flow rates through aPV-latching valve opening and closing against a range of fluidpressures.

FIG. 5B is a graphical representation of flow rates through the samePV-latching valve, using pressure/vacuum pulses of different durationsto open and close the valve.

FIG. 5C is a graphical representation of flow rates through the samePV-latching valve following a 5 s pressure or vacuum pulse to hold thevalve closed or open against a 17 kPa fluid pressure.

FIG. 6A is a diagrammatic representation of a 4-bit binary demultiplexeraddressing 16 independent V-latching valves.

FIG. 6B is a diagrammatic illustration of the demultiplexer of FIG. 6Aduring 4 of 16 possible addressing operations.

FIG. 7 is a diagrammatic representation of video frames showing themultiplexed latching valve device of FIG. 6A in operation, using abinary counting order to address the V-latching valve.

FIG. 8A is a diagrammatic representation of video frames showing themultiplexed latching valve device of FIG. 6A in operation, using a Graycode order for operating the demultiplexer.

FIG. 8B is a graphical representation of flow rates through invertedlatching valve 3, obtained while operating all 16 latching valvesaccording to the actuation pattern shown in FIG. 8A.

FIGS. 9A and 9B are diagrammatic representations of an NMOS logic gateand a membrane valve, respectively.

FIGS. 10A-10E are diagrammatic representations illustrating the layoutsof several pneumatic logic gates using membrane valves.

FIG. 11A is a graphical representation of output pressure versus controlpressure for a membrane valve.

FIG. 11B is a graphical representation of the maximum output pressureversus the number of valve transfers for a membrane valve.

FIG. 12 is a schematic view illustrating the logic diagram and truthtable for a binary full adder.

FIG. 13 is a diagrammatic representation of a pneumatic full adder.

FIG. 14 is a schematic view of the layout of a pneumatic 4-bit ripplecarry adder.

FIG. 15 is a diagrammatic view of a pneumatic 8-bit ripple carry adder.

FIG. 16A is a diagrammatic representation of selected outputs of thepneumatic 4-bit ripple carry adder of FIG. 14.

FIG. 16B is a diagrammatic representation of the output of severalrandom inputs and worse case scenarios of carry propagation for thepneumatic 8-bit ripple carry adder of FIG. 15.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to some specific embodiments of theinvention including the best modes contemplated by the inventors forcarrying out the invention. Examples of these specific embodiments areillustrated in the accompanying drawings. While the invention isdescribed in conjunction with these specific embodiments, it will beunderstood that it is not intended to limit the invention to thedescribed embodiments. On the contrary, it is intended to coveralternatives, modifications, and equivalents as may be included withinthe spirit and scope of the invention as defined by the appended claims.For example, the techniques of the present invention will be describedin the context of glass microfluidic devices, although other devicessuch as plastic or polymer devices could also be used.

It should be noted that the fluid control structures suitable for use inmicrofluidic devices can be applied to a variety of microfluidicdevices. A pathogen detection system is a good example of one possibleapplication that can benefit from the use of fluid control structures.Also, it should be noted that a fluid is considered to be an aggregateof matter in which the molecules are able to flow past each other, suchas a liquid, gas or combination thereof, without limit and withoutfracture planes forming. In the following description, numerous specificdetails are set forth in order to provide a thorough understanding ofthe present invention. The present invention may be practiced withoutsome or all of these specific details. In other instances, well knownprocess operations have not been described in detail in order not tounnecessarily obscure the present invention.

Some microfluidic devices include multichannel separation devices forhigh throughput analysis and analyzers that integrate sample preparationand analysis on a single chip. Devices that combine both multichannelanalysis and integrated sample preparation are capable of reducing theamount of resources and cost needed to perform a variety of assays. Anillustrative example may be found in the field of genomics: integrationof sequencing sample preparation, purification, and electrophoreticanalysis in a single device translates into decreases in assay time andcost and increased assay throughput efficiency and robustness. In allcases, a high level of integration in a microfluidic device requires arobust on chip mechanism for isolating, routing, merging, splitting, andstoring volumes of fluid.

Some valve technologies for use in silicon, glass silicon, polymer, andelastomer microfluidic devices have addressed these requirements in alimited manner. However, many of these technologies are chemically orphysically incompatible with many chemical or biochemical assays.Furthermore, many technologies lack the variety of robust surfacemodification chemistries available for glass microfluidic devices.Microfluidic valves that are normally open require constant actuation tomaintain fluidic control. A microfluidic device using such valves cannotbe removed from a control system without losing control of the fluidiccontents of the device. Furthermore, some devices use individuallyplaced latex membranes. Individually placed pneumatically actuated latexmembranes have been developed but this fabrication method prevents largescale integration into multichannel, high throughput analysis devices.

Other microfluidic devices are fabricated using anodically bondedsilicon and glass wafers and actuated piezoelectrically. However, theelectrical conductivity and chemical compatibility of siliconcomplicates its use in analytical devices. Thin films bonded to ordeposited on silicon can only partially mitigate the electricalconductivity and chemical compatibility.

Elastomer devices have also been demonstrated. However these structuresprovide normally open valves that are undesirable as indicated aboveHowever, the hydrophobicity and porosity of elastomeric materials renderelastomeric devices incompatible with many chemical and biochemicalassays. It is thus desirable to minimize the fluidic contact withelastomer surfaces. Complex fabrication, chemical compatibility,unreliable fluid manipulation, and other problems have made existingfluidic manipulation technologies inadequate for integration intolarge-scale, high-throughput lab-on-a-chip devices.

Consequently, the techniques and mechanisms of the present inventionprovide membrane valve structures and demultiplexers suitable for highdensity integration into microfluidic devices. A variety of fluidcontrol structures based on the membrane valves are provided, includingprocessors.

A microfluidic device having a membrane latching valve structure is oneexample of a particularly suitable device for implementing a pathogendetection system on a chip. According to various embodiments, thepathogen detection system includes immunocapture and DNA analysismechanisms such as polymerase chain reaction (PCR), and capillaryelectrophoresis (CE) mechanisms. In one example, the pathogen detectionsystem can be implemented on a glass microfluidic device having avariety of fluidic control structures.

The present invention, among other things, is directed to membrane valvestructures and demultiplexers for microfluidic devices. These structuresconsist of special assemblies of membrane valves. The normally-closednature of these valves is very important in the operation of thelatching valve structures. Latching valves can be fabricated andactuated in dense arrays, are compatible with common assay chemistries,and can be controlled by an on-chip demultiplexer. A total of 2^((n−1))independent latching valves can be controlled by n pneumatic lines.

In one embodiment, the latching valve structures may use monolithicmembrane valves. However, the present invention is not limited tomonolithic membrane valves. Membrane valves formed by, for example, amulti-step lithographic process may also be used in the presentinvention.

Devices containing monolithic membrane valves and pumps are described inW. H. Grover, A. M. Skelley, C. N. Liu, E. T. Lagally, and R. A.Mathies, Monolithic membrane valves and diaphragm pumps for practicallarge-scale integration into glass microfluidic devices, Sensors andActuators B-Chemical, 89(3):315-323, 2003 (“Grover et al.), which isincorporated herein by reference. See also, U.S. patent application Ser.No. 10/750,533, filed Dec. 29, 2003, entitled “Fluid Control StructuresIn Microfluidic Devices”, which is also incorporated herein byreference. Briefly, photolithography and wet chemical etching are usedto etch device features into glass wafers, which are then bondedtogether using a polydimethylsiloxane (PDMS) membrane sandwiched betweenthe wafers. Optionally, two or more etched or drilled glass wafers canbe thermally bonded together prior to PDMS bonding; the resultingdevices contain all-glass fluid layers that minimize fluid-PDMS contact.

Previous devices containing monolithic membrane valves and pumps tendedto have all pneumatic channels localized in one wafer (the “pneumaticwafer”) and all fluid channels localized across the PDMS membrane inanother wafer (the “fluidic wafer”). See, Grover et al. The membranevalves of the present invention contain pneumatic features (pressure orvacuum) in both wafers, and these features can be etched into eitherwafer as long as correct pneumatic and fluidic connections betweenvalves are maintained. For this reason, the pneumatic/fluidicdesignation has been abandoned in favor of a description that emphasizesconnections between the valves' inputs and outputs (previously called“valve seats” in the fluidic wafer) and controls (previously called“displacement chambers” in the pneumatic wafer).

A membrane valve 10 and the normally-closed nature of such a valve isillustrated in FIGS. 1A-1D. As shown, a PDMS membrane 12 is sandwichedbetween two wafers or substrates 14 and 16. When a vacuum is applied toa control channel 18, the membrane 12 is pulled from its valve seat 17into a displacement chamber 20 to abut against a wall 19 of thedisplacement chamber. As such, fluid is free to flow from an inputchannel 22 to an output channel 24. The nature of a glass—PDMS bondmakes the valve effective for controlling on-chip flows of gas as well.

Table 1, in which the pressures are exemplary for a particularembodiment, presents a “truth table” for pneumatic logic for the sixpossible assignments of pressure (“P”), vacuum (“V”), and no connection(“N”) (atmospheric pressure) to the control and input channels orconnections 18 and 22, respectively, of the membrane valve 10.

TABLE 1

Maintained Maintained Measured Rule at input/kPa at control/kPa atoutput/kPa PP 40 40 0 PV 40 −85 40 PN 40 0 40 VP −85 40 0 VV −85 −85 −83VN −85 0 0 P = pressure (40 kPa) V = vacuum (−85 kPa) N = no connection

The “normally closed” nature of the valve keeps the valve sealed whenequal pressures are applied to the input and control connections orchannels, and no pressure reaches the output (Rule PP). Input pressureis passed undiminished to the output if vacuum is applied to the control(Rule PV). If the input pressure is large enough to force the valveopen, the output can be pressurized even if no connection is made to thecontrol connection (Rule PN). Vacuum applied to the input connectionseals the valve against the valve seat regardless of whether there ispressure or no connection at the control (Rules VP and VN). Finally,input vacuum is passed to the output if vacuum is applied to the controlconnection (Rule VV), but the valve remains open only as long as theoutput connection is at a higher pressure than the input and controlconnections. Once the output vacuum reaches approximately 98% of theinput vacuum, the “normally closed” nature of the valve dominates andthe valve closes. By applying these rules, valve-based circuits forperforming specific on-chip tasks can be implemented.

Pneumatic logic structures that exploit the capabilities of the membranevalves may be employed. Simple three-and four-valve networks canfunction as latching valves. Other networks having a different number ofvalves may also be employed in context of the present invention. Thesevalves maintain their open or closed state even after all sources ofvacuum and pressure are removed from the device. Principles of pneumaticlogic can be used to fabricate an on-chip valve-based demultiplexer thatdistributes millisecond duration vacuum and pressure pulses to set thelatching valves open and closed. Using pneumatic logic structures, noff-chip pressure/ vacuum pneumatic control lines can be used to control2^((n−1)) independent latching valves. These pneumatic logic structuresreduce or eliminate off-chip controllers. The operation of complexlab-on-a-chip devices could be programmed into and controlled by suchon-chip pneumatic logic structures.

FIGS. 2A and 2B depict a three-valve circuit that forms avacuum-latching (“V-latching”) membrane valve structure or V-latchingvalve 30. The V-latching valve 30 includes a vacuum valve 32, a pressurevalve 34, a latching valve 36, and a vent 38. Each valve is a membranevalve formed by sandwiching a PDMS membrane between the wafers 31 and33. As shown, the features of the latching valve structure 30 are eitherformed in a top wafer 31 or a bottom wafer 33.

The vacuum valve 32 and the pressure valve 34 each include a control 40and 42, respectively. Additionally, the vacuum valve 32 and the pressurevalve 34 each include an input 44 and 46, respectively, and an output 48and 50, respectively. Likewise, the latching valve 36 includes an input52, an output 54, and a control 56. The vent 38 is open to theatmosphere. As such, it functions analogously to an electrical groundfor the valve structure 30. The valve structure 30 further includes “setpulse input” or pulse input channels 58 and 59.

The control for the latching valve 36 is connected to or in fluidcommunication with the vacuum valve 32 (responsible for holding thelatching valve open by sealing a vacuum on-chip via Rule VV) and thepressure valve 34 (responsible for eliminating the sealed on-chip vacuumvia Rule PN). The resulting circuit holds the valve open or closed aftera short vacuum or pressure pulse is applied to “set pulse input”channels 58 and 59. A related pressure/vacuum-latching (“PV-latching”)membrane valve structure or PV-latching valve 60 uses trapped vacuum tohold the latching valve 36 open and trapped pressure to hold the valveclosed against a wider range of fluid pressures. (See FIG. 3B).

In the V-latching valve 30 shown in FIGS. 2A-2B, and 3A, pulses ofpressure and vacuum in the “set pulse input” channels 58 and 59 aresupplied to the input 46 of the pressure valve 34, and the input 44 andthe control 40 of the vacuum valve 32. Since these valves are actuatedby and operate upon pressurized and depressurized air, for example, theusual references to fluidic and pneumatic connections are discarded infavor of the input, control and output connections illustrated inTable 1. The pressure, vacuum, and latching valves are normally closed(step 1 in FIG. 3A). When a pulse of vacuum is applied to the “set pulseinput” in step 2, the vacuum valve opens (Rule VV in Table 1) and thepressure valve remains closed (Rule VN). The latching volume (thechannel volume containing the outputs of the pressure and vacuum valvesand the control of the latching valve) is depressurized, and thelatching valve opens. In one embodiment, in less than 120 ms, when thelatching volume has been depressurized to approximately 98% of the setinput vacuum, the vacuum valve closes automatically (Step 3). When theset input vacuum pulse is removed in Step 4, the latching volume issealed under vacuum by the pressure and vacuum valves according to RuleVN, and the latching valve will remain latched open as long as adequatevacuum remains in the latching volume.

To close the V-latching valve 30, a pulse of pressure is applied to the“set pulse input” in step 5. Within 120 ms, this pressure forces thepressure valve open according to Rule PN in step 6, and thenow-pressurized latching volume seals the latching valve shut. When theset input pressure pulse is removed in step 7, the pressure in thelatching volume escapes as the pressure valve closes. With no pressurein the latching volume to hold it closed, the latching valve can holdoff fluid pressures, for instance, up to about 4 kPa without leakage.

The PV-latching valve 60 shown in FIG. 3B can hold off larger fluidpressures because the latching volume is pressurized while the latchingvalve 36 is latched shut (step 1 in FIG. 3B). The PV-latching valve 60is modeled after the V-latching valve 30 but includes a second pressurevalve 62, with its input 66 connected to the control of the firstpressure valve 34, its output 64 in fluid communication with or fluidlyconnected to the latching volume of valve 36, and its control 67connected to the atmosphere via a vent 68. Also, the input and output ofthe latching valve 36 is connected to or in fluid communication withports 63 and 65, respectively, for fluid flow through the valve.

In Steps 2 through 4 of FIG. 3B, a pulse of vacuum opens the PV-latchingvalve in a manner similar to the V-latching valve; the second pressurevalve 62 remains closed because of Rule VN. To close the PV-latchingvalve, a pressure pulse is applied to the “set pulse input” in step 5.Within 1 s, this pressure forces open the first pressure valve 34 byRule PN in step 6, then forces open the second pressure valve 62 by RulePN in step 7. With the latching volume and the control for the firstpressure valve all pressurized, the first pressure valve closesaccording to Rule PP. When the set input pressure is removed in Step 8,the pressure in the latching volume actively holds the first pressurevalve closed and pressure is maintained in the latching volume, therebyholding the PV-latching valve shut against fluid pressures up to about17 kPa without leakage.

Both circuits (FIGS. 3A and 3B) contain the actual latching valve andtwo or three additional pneumatic logic valves. In the V-latching valve,120 ms vacuum pulses (−85 kPa relative to atmospheric) applied to the“set pulse input” channels depressurize the latching volume and open thelatching valve in Step 4. Pressure pulses (120 ms, 40 kPa relative toatmospheric) eliminate the vacuum in the latching volume and close thelatching valve in step 7. “NC” indicates that no connection (onlyatmospheric pressure) is applied to the “set pulse input” channels. ThePV-latching valve opens in a manner similar to the V-latching valve buttraps pressure in the latching volume during closure (step 8). Thispressure seals the latching valve closed against fluid pressures as highas about 17 kPa. Gray arrows show typical amounts of time for thespecified steps.

The latching valve structures 30 and 60 were fabricated as follows.Device features were etched into glass wafers using conventionalphotolithography and wet chemical etching. Briefly, 1.1 mm thick, 100 mmdiameter borosilicate glass wafers were coated with 200 nm ofpolysilicon using low-pressure chemical vapor deposition. The waferswere then spincoated with positive photoresist, soft-baked, andpatterned with the device design using a contact aligner and a chromemask. After development and removal of irradiated photoresist, theexposed polysilicon regions were removed by etching in SF₆ plasma andthe exposed regions of the glass were etched isotropically in 49% HF toa depth of 50 μm. After stripping the remaining photoresist andpolysilicon layers, the wafers were diamond drilled with 500 μm diameterholes for pneumatic and fluidic connections. The wafers were then scoredand broken, and the resulting layers were bonded together using a 254 μmthick PDMS elastomer membrane. Optionally, two or more etched or drilledglass wafers can be thermally bonded together prior to PDMS bonding; theresulting structures contain all-glass fluid layers that minimizefluid-PDMS contact.

The latching valve structures 30 and 60 were characterized usingvariable-duration pressure (e.g., 40 kPa) and vacuum (e.g., −85 kPa)pulses from a computer-controlled solenoid valve. The pressures reportedare relative to atmospheric pressure and were measured using a straingauge pressure transducer. Flow rates through the latching valvestructures were measured by connecting a variable-height column of waterto the input of the latching valve structures. The valve output was thenconnected to a short piece of hypodermic tubing suspended in a vial ofwater on an analytical balance with 1 mg (1 μL) precision. The mass ofwater flowing through a valve structure per unit time was used todetermine the volumetric rate of flow through the valve structure and,in turn, the open or closed state of the valve structure against theapplied fluid pressure.

To test the function of the latching valve structure 30, fluid flowthrough a latching valve structure was measured while pressure andvacuum pulses of varying durations were used to actuate the valvestructure. In the first trace in FIG. 4A, 60 s of constant vacuum orpressure was applied to hold the V-latching valve open or closed. Insubsequent traces, shorter pulses of vacuum and pressure were used tolatch the latching valve open or closed. The similarity of the tracesindicates that latching valve 36 behaves identically to the constantvacuum/pressure valves 32 and 34, with only 120 ms vacuum/pressurepulses required to reliably actuate the latching valve. Shorter pulses(80 ms) still opened the latching valve reliably but were too brief forreliable closure.

To determine the long-term stability of a valve structure 30 latchedopen or closed, flow through a latched valve structure was measured forten minutes. The first trace in FIG. 4B shows that a 120 ms pressurepulse is adequate to latch the V-latching valve 30 closed for at leastten minutes. The second trace indicates that a 120 ms vacuum pulselatches the V-latching valve open for two minutes before the flow ratethrough the valve decreases by 10%. Owing to the gas permeability of thePDMS membrane, a gradual loss of vacuum in the latching volume slowlycloses the latching valve and decreases the flow rate further over thenext eight minutes.

The PV-latching valve 60 pressurizes the latching volume to hold thelatching valve 36 closed against high fluid pressures. To confirm thisbehavior, V- and PV-latching valves were fabricated with drilled holesfor measuring the pressure inside the latching volumes during valveactuation. The pressure inside the latching volume was measured while 10s pressure and vacuum pulses were used to actuate the valve. While bothvalve designs retained vacuum (−60 kPa) in the latching volumesfollowing the vacuum pulse, only the PV-latching valve 60 retainedpressure (8 kPa) after the pressure pulse.

To verify that the pressure retained in the PV-latching valve 60 holdsthe valve closed against high fluid pressures, pressure-driven fluidflow through a PV-latching valve was measured while actuating the valvewith 5 s pulses of vacuum and pressure. FIG. 5A shows that fluidpressures as high as 17 kPa were held off by the valve when latchedclosed; at 24 kPa, leakage of approximately 1 μL s⁻¹ was detectedthrough the closed valve. A premature valve closure observed only at thehighest fluid pressure (dagger) was attributed to residual pressuretrapped in the section of the pressure-latching volume between thepressure valves. This pressure leaked into the vacuum-latching volumewhile the valve was latched open, eliminating the trapped vacuum andclosing the latching valve prematurely.

In FIG. 5B, the shortest pressure pulse required for reliable sealingagainst 17 kPa fluid pressure was found to be 1 s. This is considerablylonger than the 120 ms pulse required to close the V-latching valve,probably because the two pressure valves 34 and 62 must open in seriesvia a relatively-slow Rule PN before the latching volume is pressurizedand sealed.

Finally, FIG. 5C confirms that the long-term stability of the latchedopen or closed PV-latching valve 60 compares favorably with theV-latching valve 30. A 5 s pressure pulse seals the PV-latching valveagainst 17 kPa fluid pressure for 7.5 min before flow through the valverises to 10% of the open-valve flow rate. The second trace shows that a5 s vacuum pulse holds the PV-latching valve open for 1.5 min before theflow rate drops by 10%.

A four-bit binary demultiplexer 70 shown in FIG. 6A can address 2⁴ orsixteen independent V-latching valves 30 and distribute pressure andvacuum pulses to each of them in turn. A single “set pulse input”pressure/vacuum connection 72 at the top of the device in FIG. 6Aprovides the pressure and vacuum required to actuate the V-latchingvalves. The demultiplexer contains four rows 74 of membrane valves 10,with each row containing twice the number of valves of the previous row.Each row of valves in the demultiplexer is controlled by two pneumaticconnections to a single off-chip 4/2 (four connection, two position)solenoid valve (not shown). The pneumatic connections are distributedon-chip in an alternating fashion to the demultiplexer valves in eachrow. For example, in the third demultiplexer row in FIG. 6A, pneumaticconnection “3L” controls demultiplexer valves 1, 3, 5, and 7 (numberedleft to right), and pneumatic connection “3R” controls demultiplexervalves 2, 4, 6, and 8.

When the solenoid valve controlling a particular row of demultiplexervalves is de-energized, pressure is applied to the odd-numbereddemultiplexer valves and vacuum is applied to the even-numbered valves.The even-numbered valves open and “input” pressure or vacuum from theprevious row is routed to the right into the next row of demultiplexervalves. When the solenoid valve is energized, pressure is applied to theeven-numbered demultiplexer valves and vacuum is applied to theodd-numbered valves. The odd-numbered valves open and “input” pressureor vacuum is routed to the left into the next row of demultiplexervalves.

An n-bit demultiplexer is addressed by setting each of the n rows toroute “input” pressure/vacuum to either the right or the left, and the2^(n) possible addresses range from “all right” to “all left” and everyintermediate value. For n=4, four of the sixteen possible addresses(RRRR, RRRL, RRLR, and LLLL) are illustrated in FIG. 6B. Each uniqueaddress routes the “input” pressure or vacuum to a different V-latchingvalve. By actuating the demultiplexing valves according to a cyclicpattern that selects each latching valve in turn, and applying vacuum orpressure to the “input” connection at the appropriate time to open orclose the selected latching valve, the latching valves can be opened orclosed according to any arbitrary pattern. In this manner, an n-rowdemultiplexer operated by n solenoid valves can address 2^(n)independent latching valves.

A CCD camera was used to record movies of the demultiplexer test deviceduring operation. By cycling the demultiplexer valves through allsixteen addresses in the binary counting order: RRRR, RRRL, RRLR, RRLL,RLRR, RLRL, RLLR, RLLL, LRRR, LRRL, LRLR, LRLL, LLRR, LLRL, LLLR, andLLLL, all sixteen V-latching valves are set in numerical order from 1through 16 at a rate, for example, of 190 ms per step or 3 s per cycle.

FIG. 7 represents a series of video frames showing the open/closed stateof each latching valve at each of the 32 steps in a single demultiplexercycle. Open valves appear brighter than closed valves because thestretched valve membrane forms a concave surface and reflects additionallight from a fiber optic illuminator into the CCD. In steps 1 through 16(step number), vacuum is distributed to open valves 1 through 16(latching valve number) in turn, and in steps 17 through 32 pressure isdistributed to close valves 1 through 16. Note that the state of valvethree is intentionally negated, meaning that the demultiplexer mustsuccessfully route a single 190 ms pulse of pressure (step 4) during aseries of 15 vacuum pulses, and a single 190 ms pulse of vacuum (step20) during a series of 15 pressure pulses—an especially challengingoperation for the demultiplexer.

While the observed pattern of open valves in FIG. 7 closely matches theexpected pattern (white rectangles), three errors were found (whiteovals): valve 8 closed early with valve 7 in step 24, and valve 16opened early with valve 15 in step 16 and closed early with valve 15 instep 32. Each of these errors involves a valve opening or closing earlywith the previous valve. Such errors occur when only the leastsignificant bit of the demultiplexer is switching, suggesting amalfunction associated with the least significant row of valves. Closerexamination of the binary counting pattern used to operate thedemultiplexer revealed that the least significant bit of thedemultiplexer switches with every step, causing the sixteendemultiplexer valves associated with this bit to open or close every 190ms. Errors of only a few milliseconds in the actuation of theseoverwhelmed demultiplexer valves evidently cause the observed errors.

To lessen the repetitive strain on the least significant bitdemultiplexer valves, the binary counting order was replaced by the Graycode order: RRRR, RRRL, RRLL, RRLR, RLLR, RLLL, RLRL, RLRR, LLRR, LLRL,LLLL, LLLR, LRLR, LRLL, LRRL, and LRRR. This pattern sets the sixteenlatching valves in the order 1, 9, 13, 5, 7, 15, 11, 3, 4, 12, 16, 8, 6,14, 10, and 2 at a rate of only 120 ms per step or less than 2 s percycle. Using this addressing order, demultiplexer valves are actuated atmost every other step, or every 240 ms, compared with every 190 ms forthe binary counting order.

The video frames of FIG. 8A show the open/closed state of each latchingvalve at each of the 32 steps in a single demultiplexer cycle that openseach valve in steps 1 through 16 and closes each valve in steps 17through 32 (with valve 3 still inverted). The observed pattern of openvalves exactly matches the expected pattern (white rectangles) with noerrors, proving that the demultiplexer can accurately route pressure andvacuum pulses as short as 120 ms, for example, to the intended latchingvalves.

In addition to confirming the operation of the demultiplexed latchingvalves visually, the ability of the demultiplexed valves to controlfluid was also demonstrated. FIG. 8B presents the flow of fluid throughthe inverted valve 3 while all sixteen latching valves were beingactuated according to the complex pattern in FIG. 8A. Pressure andvacuum pulses as short as 80 ms were adequate to open and close theinverted valve 3. Shorter pulses occasionally failed to open the valve,probably because of demultiplexer timing errors at fast actuation rates.

Latching pneumatic valve structures suitable for high-densityintegration into lab-on-a-chip devices have been described. Byeliminating the need for a separate off-chip controller for eachindependent valve or parallel array of valves on-chip, the latchingvalve structures of the present invention make large-scale control ofindependent valves feasible. The V-latching valves can control on-chipfluid flow in a variety of assays involving low (for example, <4 kPa)fluid pressures, and the PV-latching valves close reliably against fluidpressures up to about 17 kPa. Latching valves retain the low (˜10 nL)dead volumes found in monolithic membrane valves. Since the latchingvalve structures comprise membrane valves that can be operatedcontinuously for hours and for tens of thousands of actuations withoutfailure, it is anticipated that the long-term durability of thesestructures will be very favorable. The latching valve structures dependupon the normally-closed nature of the membrane valve. Rules PN (inputpressure breaking through an unpowered valve), VN (input vacuum sealingan unpowered valve), and VV (a valve opening to evacuate a volumeon-chip, then closing automatically to seal the volume under vacuum),all of which are essential to the operation of the latching valves,would be difficult or impossible to replicate using normally-open PDMSvalves.

The valve-based pneumatic demultiplexer uses only n off-chip pneumaticinputs to control 2^((n−1)) multiplexed latching valve structures. Inthis example, sixteen independent latching valves can be set in anyarbitrary pattern every two seconds using only five pneumatic controls.The multiplexed latching valves retain their ability to independentlycontrol fluid flow. Since the pressure, vacuum, and demultiplexer valvesthat operate the latching valves never contact the valved fluid, thepotential for cross-contamination between multiplexed latching valves iseliminated. Existing methods of on-chip logic using normally-open valveshave proved to be very useful in addressing rectilinear arrays ofmicroreactors but have not been applied to the arbitrary control ofindependent latching valves as with the present invention.

Vacuum and pressure pulses as short as 120 ms (8 valves per second) werefound to be adequate to hold the V-latching valves open and closed forat least two minutes. In two minutes, 1000 independent latching valvescan be set at a rate of 8 valves per second. This massive number ofvalves would require (log₂ 1000)+1 or only 11 off-chip pneumaticcontrols. The 10-bit demultiplexer would contain 2¹⁰⁺¹−2 or 2046 valves,and each of the 1000 V-latching valves would require two logic valves,for a total of 4046 on-chip logic valves to control 1000 latchingvalves. If each logic valve and its associated pneumatic channels occupy2 mm², 4000 logic valves could be fabricated using photolithography intoa single glass PDMS—glass layer of a 10 cm diameter microfluidic device.One surface of this layer could then be bonded to additional wafersthrough another PDMS membrane, thereby forming a fluidic layer for theplacement of the 1000 independent latching valves in the desired assayconfiguration. The prospect that a single additional layer in alab-on-a-chip device could eliminate literally hundreds of off-chipsolenoid valves, relays, and computers attests to the potential ofpneumatic logical structures.

By reducing the off-chip control equipment necessary for the operationof microfluidic devices, multiplexed latching pneumatic valve structuresshould play an important role in making low-cost, low-power, andhand-held lab-on-a-chip analysis devices a reality. Analysis deviceswith fewer off-chip solenoid valves and electronic control circuitswould consume less power and be better suited for battery-operated fielduse. Critically, in robotic analysis systems for space exploration,eliminating off-chip controllers would conserve sparse payload space andpower. Also note that the pneumatic logic circuits like thedemultiplexer presented here are immune to high energy particles, solarflares, and electromagnetic pulse interference, which can irreparablydamage electronic logic circuits.

The present invention also establishes the basis for pneumatic logicgates, for example, generic, valve-based AND, OR, and NOT structures,which can be arranged into circuits or programs that encode and controlthe operation of any microfluidic device. In a classic example, flowthrough two membrane valves connected in series is allowed only if bothvalves are open—a logical AND. Similarly, flow through two membranevalves connected in parallel is possible if either (or both) of thevalves is open—a logical OR. The feedback loops used to hold thelatching valve open in the V-latching valve and closed in thePV-latching valve are closely analogous to NAND- and NOR-based latchcircuits used as binary memories in electronic circuits. See, C. H.Roth, Jr., Fundamentals of logic design, West Publishing Company, 1985,which is incorporated herein by reference. These logical operations formthe foundations of all electronic computations. It is believed thatmicrofluidic logic structures of the type of the present invention willprove to be fundamentally useful in the assembly of complex pneumaticprocessors. It is also noted that the present invention is not limitedto use with the particular logic gates specifically illustrated anddescribed. The concept of the present invention may be used to constructvarious different logic gates and circuits.

FIGS. 9A and 9B illustrate the relationship between a NMOS logic gate 80and its implementation with a normally-closed, pneumatically actuatedmembrane valve 90 of the type described above. (See, FIG. 1). Theapplication of a voltage to a control input terminal 82 of the N-MOSFETinduces a current of electrons from the ground to the positive voltagepower supply (V_(dd)), resulting in a significant decrease in the outputvoltage (false output). Similarly, the application of a vacuum to anoperand input 92 of a pneumatic inverter opens the valve, resulting in acurrent of air from the vent 94 (hole to atmosphere) to a gate controlinput 95 which is supplied with a vacuum. This decreases the vacuummagnitude in the output channel 96 to a level that is insufficient forthe actuation of downstream valves (pneumatic false). In both systems, astatic current (electrical or pneumatic) flows during a logic lowoutput, and a logic high output results when the input is false.

The pneumatic logic device of the present invention may be fabricated asdiscussed above. For device characterization, pneumatic inputs weresupplied by the actuation of computer controlled solenoid valves for theevaluation of individual microvalves, logic gates, and the addercircuits. Separate pumps were used to supply logic high and logic lowpressures to the solenoid valves. Pneumatic signals were conducted fromthe solenoid valves to the drilled chip inputs using polyurethane tubingwith a 1.6 mm internal diameter and lengths ranging from 15-30 cm.Pressure measurements reported for single valves, logic gates, and thefull adders are relative to atmospheric and were measured using a straingauge pressure transducer (PM 100D, World Precision Instruments).Digital videos of the operation of 4 and 8-bit adders were recordedusing a CCD camera.

Pneumatic logic gates are composed of networks of valves to whichpneumatic signals are applied via gate input channels. Vacuums greaterthan −20 kPa, for example, are capable of valve actuation and thereforerepresent a logic high, or the “true” value of digital logic.Sub-threshold vacuum magnitudes represent a logic low, or the “false”value.

FIGS. 10A-10E show the layout of several pneumatic logic gates thatoperate similarly to NMOS logic gates. Each logic gate requires one ormore gate control input (Ctrl) channels to which constant vacuum isapplied during digital logic operations. Operand gate input channels (Aand B) are supplied with −76 kPa as a logic high and 6 kPa as a logiclow. A pneumatic AND gate 100 (FIG. 10A) is composed of two microvalves90 connected in series. Vacuum will only be transmitted from the inputto the output if both valves are actuated simultaneously. Similarly, apneumatic OR gate 102 (FIG. 10B) is composed of two microvalves 90connected in parallel. The pneumatic NAND gate 104 shown in FIG. 10C isa universal logic gate (a gate from which any logical function may bebuilt) that functions similarly to a NOT gate. For this logic gate, theoutput is false if both inputs are true, and the output is true in allother cases.

Combinations of the AND, OR and NOT gates are also capable of universallogic operations. For instance, the pneumatic XOR 106 (FIG. 10D) iscomposed of a combination of NOT gates and OR gates. When only one ofthe operand inputs (A and B) is true, the Ctrl 1 input vacuum istransmitted to either X1e or X1f resulting in a logic high output. Whenboth operand inputs are true, the opening of valves X1a and X1d createsa direct connection between the Ctrl 1 input and two vents 105 and 107to the atmosphere. In this case neither X1e nor X1f are actuated, and novacuum is transmitted to the output.

The buffer circuit 108 shown in FIG. 10E amplifies an input vacuumsignal and enables successful signal propagation in more complexpneumatic logic circuits. This pneumatic buffer circuit is based on therelation, NOT(NOT(A))=A. With both control inputs held at about −87 kPa,application of a weaker vacuum to the operand input (A) opens valve b1.The opened connection to atmospheric pressure decreases the vacuuminduced by the Ctrl 2 input, resulting in the closure of the valve b2.When valve b2 is closed, the full magnitude of the Ctrl 1 input istransmitted to the output.

As discussed, when the same vacuum magnitude is applied to the controland input channels of a single valve, the valve closes after the outputchannel has reached approximately 98% of the input and control vacuum.This feature can be used for the development of bistable latching valvecircuits.

To characterize the pneumatic signal transduction through microvalves asa function of control channel pressure, individual valve input channelswere supplied with a constant pressure of −87 kPa while the pressure inthe control channels was varied using a separate vacuum pump. FIG. 11Ashows a linear increase in output vacuum magnitude with increasingcontrol vacuum magnitude. Since the slope of this curve (1.5) is greaterthan 1, a linear network in which the output of valve n is the controlinput of valve n+1 will exhibit an exponential decrease in output vacuummagnitude with increasing n. (FIG. 11B). This imposes a practical limiton the integration of pneumatic logical structures that do not employ asignal amplification mechanism such as the buffer circuit describedabove.

Since binary addition is used in a wide range of computing operationsincluding subtraction and multiplication, it plays an important role inthe operations performed by the CPU of a modern computer. FIG. 12 showsthe logic diagram and truth table of a binary full adder 110. Theoperand inputs (A, B, and Carry In) are processed by a circuit of AND,OR and XOR gates resulting in two outputs, Sum and Carry Out. The truthtable shows the expected logical outputs for all possible combinationsof input values.

A pneumatic full adder 120 (FIG. 13) is composed of two XOR gates 122and 124, and a hybrid OR gate 126 in which two AND gates are aligned inparallel. Four gate control inputs (Ctrl X1, Ctrl X2, Ctrl X1X2, andCtrl C) are required for the operation of this circuit. From the restingstate in which each valve is closed, all of the operand and control gateinputs are actuated simultaneously with the exception of X2 which isactuated after a 250 ms delay. This delay is necessary since the XOR2gate processes the output of XOR1, which has a corresponding gate delay.

In a ripple-carry adder, multiple full-adders are chained together withthe Carry Out of one adder connected to the Carry In of the next mostsignificant adder. FIG. 14 shows the schematic layout of a pneumatic4-bit ripple carry adder 130. During carry propagation, the pneumaticCarry Out of the adder may pass through a 2 mm diameter via hole in thePDMS membrane before actuating valves in an adjacent adder as the carryinput. Each X1X2 control input is connected on-chip through a channelnetwork that leads to a single drilled input hole (vent). A similar businput system was designed for the Ctrl C inputs, whereas the X1 and X2control inputs were separately combined using off chip tubing. Sinceeach of the full adder control inputs are supplied with pneumaticsignals in parallel through bus channels or off-chip tubing, only fouroff-chip controllers are required to actuate all of the control inputsof multi-bit adders. The output channels for sums and the final CarryOut convey pneumatic signals to a linear array of valves used as areadout of the computed sum. Half adders were incorporated into thecircuits for addition of the least significant bits in the multi-bitadders.

In an pneumatic 8-bit ripple-carry adder 140, (FIG. 15), a similar busarchitecture can be used to actuate the control inputs of the adders inparallel. The adders 141-148 are arrayed radially with output channels150 for sums and the final carry extending to a linear array of readoutvalves 152 in the center of the chip. A buffer circuit 154 can be usedto the Carry Out of the fourth adder to amplify the signal and ensuresuccessful carry propagation through any number of the adders.

The propagation times and output magnitudes of each individual logicgate in FIGS. 10A-10E were characterized on a single fabricated device.For each logic gate, operand and control inputs were actuatedsimultaneously. Each logic gate generated output vacuum magnitudes thatfall into the correct ranges for logic high or logic low as discussedabove. The lowest magnitude for a logic high output was observed for theXOR gate (−63 kPa), since it is composed of the most complex network ofvalves. Latching of the output vacuum occurs in the XOR gate if all ofthe inputs are turned off simultaneously. This latched volume wouldeventually be restored to atmospheric pressure due to the gaspermeability of the PDMS membrane; however, the process can be expeditedby actuating the operand inputs while the control inputs are closed.Dynamic response times were defined as the interval between theactuation of off-chip solenoid valves and the opening of an outputmicrovalve due to a logic high output. The longest response time (250ms) was observed for the XOR gate. Since these response times include adelay due to the evacuation of tubing between the solenoid valves andthe chip inputs, optimization of vacuum pump speed and the dimensions ofoff-chip tubing may significantly improve the speed of logicaloperations.

Table 2 is a truth table (in kPa) illustrating the output vacuum andpressure magnitudes of the pneumatic full adder 120 (FIG. 13) for allpossible combinations of inputs.

TABLE 2 A B Carry In Sum Carry Out 6 6 6 0 0 −87 6 6 −46 0 6 −87 6 −48 0−87 −87 6 0 −65 6 6 −87 −64 0 −87 6 −87 0 −55 6 −87 −87 0 −54 −87 −87−87 −65 −65

As an example, the Carry Out is true when both XOR(A,B) is true and theCarry In is true. In these cases, the output of XOR1 is transferred tothe control input of valve C4 (FIG. 13). The input of this valve issupplied with a ˜−87 kPa signal via the Ctrl C gate input channel. Basedon the −64 kPa logic high output of an individual XOR gate, and usingthe equation for the linear regression in FIG. 11A, a Cout vacuum of −54kPa is predicted. This agrees with the experimentally determined valuesfrom the pneumatic full-adder. The operation of the full adder requireda 250 ms delay for the actuation of the X2 control input. Delays lessthan 250 ms are insufficient for the transfer of output from XOR1 to theinput of XOR2 and therefore result in incorrect output sums. To avoidlatching of gates within the adder, an 8-step, 2 second closingprocedure can be used to expedite a return to the resting state. Morecomplex closing procedures are not required for multi-bit adders sincethe closing program can be applied to each adder in parallel. No vacuumis transmitted to the Carry Out or Sum outputs during these closingprocedures.

FIG. 16A shows selected outputs of the pneumatic 4-bit binary adder 130.(FIG. 14). Each row is a digital image of the output valve array takenafter actuation with the indicated pattern of inputs. Open valvesreflect more light and appear brighter than closed valves. Simultaneousactuation of all inputs except the X2 bus results in the automaticpropagation of carry information throughout the system. The addition of1111 and 0001 generates a carry in the least significant bit that ispropagated through all of the other adders and results in the outputsum, 10000. This represents a worst case scenario for the time requiredto compute a sum and was used to determine a reliable actuation delayfor the XOR2 bus. Correct outputs were reliably obtained for each of the256 possible pneumatic inputs configurations using a 500 ms XOR2actuation delay.

FIG. 16B shows the output of several random inputs and worst casescenarios of carry propagation for the pneumatic 8-bit binary adder 140.(FIG. 14). The control inputs of the buffer circuit were powered byconstant vacuum during the operation of the device, and a 1.1 seconddelay was used for the actuation of the X2 bus input. Previous designsthat did not include the amplifier structure failed due to loss ofsignal during carry propagation. Particularly challenging cases arisewhen a weak carry signal must open a valve closed with a vacuum appliedto its input channel. This is the case during the computation of01111111+00000001 in which valve X2f is opened in the most significantadder by a propagated carry signal.

The membrane valves function like the transistors in conventional TTLlogical circuits. These pneumatic “transistors” can be assembled intovariety of basic gate structures (AND, OR, NOT, NAND, and XOR), and theycan be combined to form computational circuits for binary addition. Thedevelopment of an amplifying buffer circuit allows the extension of thetechnology to 8-bit binary adder circuits in which pneumatic signalsmust propagate through numerous gates. This suggests that more complexlogical circuits, such as the significantly faster carry-lookaheadadder, could be developed using the design principles discussed above.

Future modeling of the mechanics of individual valves and airflowthrough valve networks will allow precise optimization for improvedresponse times. It has been noted that pneumatic logical devices arelimited by the speed of sound in air. Although this limitation preventsany serious competition with digital electronics for computing speed,actuation frequencies in the millisecond scale are commonly used inlab-on-a-chip devices and should be attainable using micropneumaticlogic. Furthermore, the miniaturization and integration of controlsystems may be especially useful for the development of portable MEMSdevices for pathogen detection or extraterrestrial biomarker analysis.

The timing of valve actuation can be integrated using micropneumaticlogical structures. As the carry propagates through a multi-bitmicropneumatic adder, an automatic series of valve actuations occurs ina precise time sequence. Similarly, in digital electronics, delaycircuits are often used to synchronize operational sequences in signalprocessing units. As noted previously, the latching behavior of networksof valves resembles the function of simple memory circuits such asflip-flops. These features could be exploited in future integratedsystems that implement dynamic logical control. For situations in whichlatching behavior is disadvantageous, channels joining the valves in anetwork can be modeled as an RC circuit with a capacitance andresistance to the ground (atmospheric pressure). Smaller valves andchannels would decrease the network capacitance, and nano-scale leakchannels or membranes with altered gas permeability may increase airflowto the latched volumes from the atmosphere without significantlydecreasing output signals during a logical operation. Such a system forreducing the latching characteristics of microvalve networks will resultin improved performance and obviate the closing procedures requiredhere.

Integrated pneumatic logic structures have proven useful for thedevelopment of valve latching structures and multiplexed control ofvalve arrays in complex lab-on-a-chip applications. The logic of amicrofluidic device can be encoded in a membrane valve array, forexample, on a chip. Inputs are provided to the membrane valve array andlogically executed. This enables the membrane valve array to control amicrofluidic process of an assay performed on the chip. An input to andan output from the membrane valve array may be constant or vary withintime.

Further development in this area will catalyze progress toward thecreation of multi-purpose, programmable microfluidic devices that can beutilized for diverse analyses. Miniaturized pneumatic logic structuresmay also allow integrated control in microassembly and microroboticsystems which often employ pneumatic actuation mechanisms. Furthermore,the present invention could be used to develop simple computing systemsthat are immune to radio frequency or pulsed electromagneticinterference. Such computing devices may also be useful in extremeenvironments such as those of space missions, where cosmic rays resultin the malfunction or failure of electronic components.

Although certain of the components and processes are described above inthe singular for convenience, it will be appreciated by one of skill inthe art that multiple components and repeated processes can also be usedto practice the techniques of the present invention.

While the invention has been particularly shown and described withreference to specific embodiments thereof, it will be understood bythose skilled in the art that changes in the form and details of thedisclosed embodiments may be made without departing from the spirit orscope of the invention. For example, the embodiments described above maybe implemented using a variety of materials. Therefore, the scope of theinvention should be determined with reference to the appended claims.

1. A membrane latching valve structure comprising: first and secondinput channels; a first membrane valve having an input in fluidcommunication with the first input channel and a control of the firstmembrane valve in fluid communication with atmospheric; a secondmembrane valve having an input in fluid communication with the firstinput channel, an output in fluid communication with an output of thefirst membrane valve, and a control in fluid communication with thesecond input channel; a third membrane valve having a control in fluidcommunication with the output of the first membrane valve and the outputof the second membrane valve; such that when a sufficient vacuum isapplied to the first and second input channels, the third membrane valvemoves to an open position and is latched in that position when thevacuum is removed; and such that when a sufficient pressure is appliedto the first and second input channels, the third membrane valve movesto a closed position and is latched in that position when the pressureis removed.
 2. The membrane latching valve structure of claim 1 whereinan input and output of the third membrane valve is configured to form aninput and output of the membrane latching-valve structure.
 3. Themembrane latching valve structure of claim 1 wherein the second inputchannel, the control of the first membrane valve, the control of thesecond membrane valve, and the input and output of the third membranevalve are formed in a first surface.
 4. The monolithic membrane latchingvalve of claim 3 wherein the first input channel, the input and outputof the first membrane valve, the input and output of the second membranevalve, and the control of the third membrane valve are formed in asecond surface opposite the first surface.
 5. The monolithic membranelatching valve structure of claim 4 wherein an elastomer membrane islocated between the first and second surfaces at the area of the controlof the first, second and third membrane valves such that the applicationof a pressure or a vacuum at the first and second input channels causesthe membrane to deflect to modulate a flow of a fluid through the first,second, or third membrane valve.
 6. The membrane latching valvestructure of claim 1 further including: a fourth membrane valve havingan input in fluid communication with the control of the third membranevalve, an output in fluid communication with the control of the firstmembrane valve, and a control in fluid communication with atmospheric.7. The membrane latching valve of claims 1 wherein there are a pluralityof membrane latching valve structures and further including amicrofluidic demultiplexer configured to address each of the membranelatching valve structures with either a vacuum or a pressure pulse. 8.The membrane latching valve structure of claim 7 wherein thedemultiplexer includes a plurality of rows of membrane valves configuredto distribute the pressure and vacuum pulses to each of the membranelatching valve structures.
 9. The membrane latching valve structure ofclaim 8 further including two pneumatic connections for each row ofmembrane valves of the demultiplexer.
 10. The membrane latching valvestructure of claim 8 wherein the demultiplexer has n- rows of membranevalves operated by n- solenoid valves to address 2n independent membranelatching valve structures.
 11. The membrane latching valve structure ofclaim 8 wherein each row after the first row of membrane valves hastwice the number of membrane valves of the previous row.
 12. A membranevalve structure comprising: a first input channel formed in a firstsurface of a first substrate; a second input channel formed in a secondsurface of a second substrate; a pressure valve having a control formedin the first surface and fluidly connected with atmospheric, and aninput and output formed in the second surface wherein the input isfluidly connected to the second input channel; a vacuum valve having acontrol formed in the first surface and fluidly connected to a firstinput channel, and input and an output formed in the second surface suchthat the input is fluidly connected to the second input channel; alatching valve having an input and output formed in the first surface,and a control formed in the second surface such that the control isfluidly connected to the output of the vacuum valve; and an elastomermembrane located between the first and second surfaces at the area ofthe control of each of the pressure, vacuum and latching valves suchthat the application of a pressure or a vacuum to the first and secondinput channels causes the membrane to deflect to modulate a flow of afluid through the valves.
 13. A microfluidic logic circuit comprising:an array of membrane valves, each valve including a valve input, a valveoutput, a valve control, and an elastomer membrane wherein theapplication of a pressure or a vacuum can cause the membrane to deflectto modulate a flow of fluid through the valve, and wherein the membranevalves are connected in fluid communication with each other such that apneumatic input to the array or membrane valves is logically operatedupon to produce a pneumatic output.
 14. The microfluidic logic circuitof claim 13 wherein the array of membrane valves includes two membranevalves configured to form an AND gate or an OR gate.
 15. Themicrofluidic logic structure of claim 13 wherein the array of membranevalves is configured to form a NAND gate or an XOR gate.
 16. Themicrofluidic logic circuit of claim 13 wherein the array of membranevalves is configured to form a buffer circuit.
 17. The microfluidiclogic circuit of claim 13 wherein the array of membrane valves isconfigured to form a ripple carrier adder.